tbuckley/cabot-search huggingface dataset:
SWI/SNF Blockade Disrupts PU.1-Directed Enhancer Programs in Normal Hematopoietic Cells and Acute Myeloid Leukemia
Authors: Courtney Chambers, Katerina Cermakova, Yuen San Chan, Kristen Kurtz, Katharina Wohlan, Andrew Henry Lewis, Christiana Wang, Anh Pham, Milan Dejmek, Michal Sala, Mario Loeza Cabrera, Rogelio Aguilar, Radim Nencka, H. Daniel Lacorazza, Rachel E. Rau, H. Courtney Hodges
Journal: Cancer Research (2023)

Abstract In acute myeloid leukemia (AML), SWI/SNF chromatin remodeling complexes sustain leukemic identity by driving high levels of MYC. Previous studies have implicated the hematopoietic transcription factor PU.1 (SPI1) as an important target of SWI/SNF inhibition, but PU.1 is widely regarded to have pioneer-like activity. As a result, many questions have remained regarding the interplay between PU.1 and SWI/SNF in AML as well as normal hematopoiesis. Here we found that PU.1 binds to most of its targets in a SWI/SNF-independent manner and recruits SWI/SNF to promote accessibility for other AML core regulatory factors, including RUNX1, LMO2, and MEIS1. SWI/SNF inhibition in AML cells reduced DNA accessibility and binding of these factors at PU.1 sites and redistributed PU.1 to promoters. Analysis of nontumor hematopoietic cells revealed that similar effects also impair PU.1-dependent B-cell and monocyte populations. Nevertheless, SWI/SNF inhibition induced profound therapeutic response in an immunocompetent AML mouse model as well as in primary human AML samples. In vivo, SWI/SNF inhibition promoted leukemic differentiation and reduced the leukemic stem cell burden in bone marrow but also induced leukopenia. These results reveal a variable therapeutic window for SWI/SNF blockade in AML and highlight important off-tumor effects of such therapies in immunocompetent settings. Significance: Disruption of PU.1-directed enhancer programs upon SWI/SNF inhibition causes differentiation of AML cells and induces leukopenia of PU.1-dependent B cells and monocytes, revealing the on- and off-tumor effects of SWI/SNF blockade.
European Academy of Allergy and Clinical Immunology position paper on endoscopic scoring of nasal polyposis
Authors: Philippe Gevaert, Jarno De Craemer, Claus Bachert, Manon Blauwblomme, Adam Chaker, Cemal Cingi, Peter W. Hellings, Claire Hopkins, Valérie Hox, Wytske J. Fokkens, Ludger Klimek, Valerie Lund, Ralph Mösges, Joaquim Mullol, Oliver Pfaar, Glenis Scadding, Peter Valentin Tomazic, Thibaut Van Zele, Stephan Vlaminck, Martin Wagenmann, Sanna Toppila‐Salmi, Isam Alobid
Journal: Allergy (2023)

Nasal endoscopy is not only used for the diagnosis of chronic rhinosinusitis with nasal polyps (CRSwNP), but also for monitoring the response to therapy playing an important role in both daily practice and research. In contrast to patient-reported outcomes, endoscopic nasal polyp scoring by independent blinded readers is an objective measurement, not influenced by the placebo effect. It is safer and cheaper compared with computed tomography imaging and therefore, better suited for regular assessments of the extent of the disease. Since the early 90s, a variety of endoscopic staging methods have been proposed and used in clinical research, making it hard to compare results from different studies. This paper resulted from a task force with experts in the field of CRSwNP, originated by the Ear, Nose and Throat section of the European Academy of Allergy and Clinical Immunology and aims to provide a unified endoscopic NP scoring system that can serve as a reference standard for researchers, but also as a useful tool for practitioners involved in the management of CRSwNP.
How Many Sirtuin Genes Are Out There? Evolution of Sirtuin Genes in Vertebrates With a Description of a New Family Member
Authors: Juan C Opazo, Michael W Vandewege, Federico G Hoffmann, Kattina Zavala, Catalina Meléndez, Charlotte Luchsinger, Viviana A Cavieres, Luis Vargas-Chacoff, Francisco J Morera, Patricia V Burgos, Cheril Tapia-Rojas, Gonzalo A Mardones
Journal: Molecular Biology and Evolution (2023)

Studying the evolutionary history of gene families is a challenging and exciting task with a wide range of implications. In addition to exploring fundamental questions about the origin and evolution of genes, disentangling their evolution is also critical to those who do functional/structural studies to allow a deeper and more precise interpretation of their results in an evolutionary context. The sirtuin gene family is a group of genes that are involved in a variety of biological functions mostly related to aging. Their duplicative history is an open question, as well as the definition of the repertoire of sirtuin genes among vertebrates. Our results show a well-resolved phylogeny that represents an improvement in our understanding of the duplicative history of the sirtuin gene family. We identified a new sirtuin gene family member (SIRT3.2) that was apparently lost in the last common ancestor of amniotes but retained in all other groups of jawed vertebrates. According to our experimental analyses, elephant shark SIRT3.2 protein is located in mitochondria, the overexpression of which leads to an increase in cellular levels of ATP. Moreover, in vitro analysis demonstrated that it has deacetylase activity being modulated in a similar way to mammalian SIRT3. Our results indicate that there are at least eight sirtuin paralogs among vertebrates and that all of them can be traced back to the last common ancestor of the group that existed between 676 and 615 millions of years ago.
Immunology of Giant Cell Arteritis
Authors: Cornelia M. Weyand, Jörg J. Goronzy
Journal: Circulation Research (2023)

Giant cell arteritis is an autoimmune disease of medium and large arteries, characterized by granulomatous inflammation of the three-layered vessel wall that results in vaso-occlusion, wall dissection, and aneurysm formation. The immunopathogenesis of giant cell arteritis is an accumulative process in which a prolonged asymptomatic period is followed by uncontrolled innate immunity, a breakdown in self-tolerance, the transition of autoimmunity from the periphery into the vessel wall and, eventually, the progressive evolution of vessel wall inflammation. Each of the steps in pathogenesis corresponds to specific immuno-phenotypes that provide mechanistic insights into how the immune system attacks and damages blood vessels. Clinically evident disease begins with inappropriate activation of myeloid cells triggering the release of hepatic acute phase proteins and inducing extravascular manifestations, such as muscle pains and stiffness diagnosed as polymyalgia rheumatica. Loss of self-tolerance in the adaptive immune system is linked to aberrant signaling in the NOTCH pathway, leading to expansion of NOTCH1
Pros and Cons of Long-Chain Omega-3 Polyunsaturated Fatty Acids in Cardiovascular Health
Authors: Ivana Djuricic, Philip C. Calder
Journal: The Annual Review of Pharmacology and Toxicology (2023)

The long-chain omega-3 fatty acids, eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are found in seafood, supplements, and concentrated pharmaceutical preparations. Prospective cohort studies demonstrate an association between higher intakes of EPA+DHA or higher levels of EPA and DHA in the body and lower risk of developing cardiovascular disease (CVD), especially coronary heart disease and myocardial infarction, and of cardiovascular mortality in the general population. The cardioprotective effect of EPA and DHA is due to the beneficial modulation of a number of risk factors for CVD. Some large trials support the use of EPA+DHA (or EPA alone) in high-risk patients, although the evidence is inconsistent. This review presents key studies of EPA and DHA in the primary and secondary prevention of CVD, briefly describes potential mechanisms of action, and discusses recently published RCTs and meta-analyses. Potential adverse aspects of long-chain omega-3 fatty acids in relation to CVD are discussed.
How do we enhance protective immunity to COVID-19 in lung transplant recipients?
Authors: David W.J. Griffin, James H. McMahon
Journal: European Respiratory Journal (2023)

<b>A more nuanced understanding of the immunological factors protecting lung transplant recipients from COVID-19 infection and severe disease are urgently required, including the roles for additional booster doses and immunosuppression modification</b>https://bit.ly/3C8dOlq
A fond farewell
Authors: Robert M. Frederickson
Journal: Molecular Therapy (2023)

It’s been a fun ride, but all good things must come to an end. I decided to step down from my post as executive editor of the Molecular Therapy (MT) family of journals on December 31 of last year. When I took on this job over two decades ago, the field of gene and cell therapy looked quite different than it does now, as did the journal. MT was ASGCT’s sole journal at the time, and it netted the Society very little revenue. There were no approved gene therapy products on the market, and the appetite of investors to get into the gene and cell therapy space was quite low. The MT family now comprises four journals operating under a far more sustainable and productive revenue model in cooperation with ASGCT’s publishing partner, Cell Press. There are several gene therapy products available around the world, with many more soon to come.
The IL-4Rα Q576R polymorphism is associated with increased severity of atopic dermatitis and exaggerates allergic skin inflammation in mice
Authors: Barbara Yang, Hazel Wilkie, Mrinmoy Das, Maheshwor Timilshina, Wayne Bainter, Brian Woods, Michelle Daya, Meher P. Boorgula, Rasika A. Mathias, Peggy Lai, Carter R. Petty, Edie Weller, Hani Harb, Talal A. Chatila, Donald Y.M. Leung, Lisa A. Beck, Eric L. Simpson, Tissa R. Hata, Kathleen C. Barnes, Wanda Phipatanakul, Juan-Manuel Leyva-Castillo, Raif S. Geha
Journal: Journal of Allergy and Clinical Immunology (2023)
Serum IFN-γ and RNAemia temporal profiles as biomarkers of severe COVID-19 in solid organ transplant and immunocompetent patients
Authors: Sonsoles Salto-Alejandre, Marta Carretero-Ledesma, Pedro Camacho-Martínez, Judith Berastegui-Cabrera, Carmen Infante, Regino Rodríguez-Álvarez, Jorge Alba, Patricia Pérez-Palacios, Emilio García-Díaz, Cristina Roca, Julia Praena, María José Blanco-Vidal, Sonia Santibáñez, Rocío Valverde-Ortiz, Javier Nieto-Arana, Concepción García-García, David Gutiérrez-Campos, Natalia Maldonado, Gabriel Bernal, Miguel Ángel Gómez-Bravo, José Manuel Sobrino, Manuela Aguilar-Guisado, Rocío Álvarez-Marín, Josune Goikoetxea-Aguirre, José Antonio Oteo, Zaira R. Palacios-Baena, Álvaro Pascual, José Antonio Lepe, Jesús Rodríguez-Baño, José Miguel Cisneros, Jerónimo Pachón, Javier Sánchez-Céspedes, Elisa Cordero
Journal: Journal of Infection (2023)
Alternative forms of portal vein revascularization in liver transplant recipients with complex portal vein thrombosis
Authors: Yiliam Fundora, Amelia J. Hessheimer, Luca Del Prete, Lorenzo Maroni, Jacopo Lanari, Oriana Barrios, Mathias Clarysse, Mikel Gastaca, Manuel Barrera Gómez, Agnès Bonadona, Julius Janek, Andrea Boscà, Jose María Álamo Martínez, Gabriel Zozaya, Dolores López Garnica, Paolo Magistri, Francisco León, Giulia Magini, Damiano Patrono, Jiří Ničovský, Abdul Rahman Hakeem, Silvio Nadalin, Lucas McCormack, Pilar Palacios, Krzysztof Zieniewicz, Gerardo Blanco, Javier Nuño, Baltasar Pérez Saborido, Juan Echeverri, J. Steve Bynon, Paulo N. Martins, Víctor López López, Murat Dayangac, J. Peter A. Lodge, Renato Romagnoli, Christian Toso, Julio Santoyo, Fabrizio Di Benedetto, Concepción Gómez-Gavara, Fernando Rotellar, Miguel Ángel Gómez-Bravo, Rafael López Andújar, Edouard Girard, Andrés Valdivieso, Jacques Pirenne, Laura Lladó, Giacomo Germani, Matteo Cescon, Koji Hashimoto, Cristiano Quintini, Umberto Cillo, Wojciech G. Polak, Constantino Fondevila
Journal: Journal of Hepatology (2023)
Advocating for patients with skin disease: Federal dermatology lobbying and expenditure activity by the American Academy of Dermatology Association and SkinPAC from 2008 to 2021
Authors: Samir Kamat, Joseph Han, Aneesh Agarwal, Yen Luu, Jacob M. Appel, George J. Hruza, Phillip M. Singer
Journal: Journal of the American Academy of Dermatology (2023)
Correction: CircNTNG1 inhibits renal cell carcinoma progression via HOXA5-mediated epigenetic silencing of Slug
Authors: Yanping Liang, Junjie Cen, Yong Huang, Yong Fang, Yunfei Wang, Guannan Shu, Yihui Pan, Kangbo Huang, Jiaqi Dong, Mi Zhou, Yi Xu, Junhang Luo, Min Liu, Jiaxing Zhang
Journal: Molecular Cancer (2023)

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Dose–response effects of exercise and caloric restriction on visceral adiposity in overweight and obese adults: a systematic review and meta-analysis of randomised controlled trials
Authors: Francesco Recchia, Chit K. Leung, Angus P. Yu, Welton Leung, Danny J. Yu, Daniel Y. Fong, David Montero, Chi-Ho Lee, Stephen H.S. Wong, Parco M. Siu
Journal: British Journal of Sports Medicine (2023)

Objective To determine and compare the dose–response effects of exercise and caloric restriction on visceral adipose tissue in overweight and obese adults, while controlling for the weekly energy deficit induced by the interventions. Methods PubMed, Embase, CINAHL and Web of Science were searched for randomised controlled trials comparing exercise or caloric restriction against eucaloric controls in overweight or obese adults. The primary outcome was the change in visceral fat measured by CT or MRI. Meta-analyses and meta-regressions were performed to determine the overall effect size (ES) and the dose–dependent relationship of exercise and caloric restriction on visceral fat. Heterogeneity, risk of bias and the certainty of evidence were also assessed. Results Forty randomised controlled trials involving 2190 participants were included. Overall, exercise (ES −0.28 (−0.37 to −0.19); p&lt;0.001; I 2 =25%) and caloric restriction (ES −0.53 (−0.71 to −0.35); p&lt;0.001; I 2 =33%) reduced visceral fat compared with the controls. Exercise demonstrated a dose–response effect of −0.15 ((−0.23 to −0.07); p&lt;0.001) per 1000 calories deficit per week, whereas the effect of caloric restriction was not dose-dependent (ES 0.03 (−0.12 to 0.18); p=0.64). Most of the studies showed a moderate risk of bias. Conclusions These findings support the dose–dependent effects of exercise to reduce visceral fat in overweight and obese adults. Caloric restriction did not demonstrate a dose–response relationship, although this may be attributed to the smaller number of studies available for analysis, compared with exercise studies. PROSPERO registration number CRD42020210096.
When I use a word . . . . Medical anniversaries in 2023: Théodore de Mayerne
Authors: Jeffrey K Aronson
Journal: BMJ (2023)

2023 is the 450th anniversary of the birth of the Swiss-born Huguenot physician Théodore de Mayerne on 28 September 1573. After graduating in medicine in Montpelier and making a Grand Tour of Europe, including visits to Queen Elizabeth I in London and James VI in Edinburgh, Mayerne returned to France. However, increasing persecution of the Huguenots in France and an offer of a position as a personal physician in England led Mayerne to return to England in 1611, where he became a physician to King James I and a fellow of the College of Physicians of London. With Henry Atkins he encouraged the publication by the college of the <i>Pharmacopoeia Londinensis</i> in 1618, which came to 11 editions over the next 33 years and laid the foundations for other national pharmacopoeias, including the <i>Edinburgh Pharmacopoeia</i> (1699) and the <i>Dublin Pharmacopoeia</i> (1807). It was eventually replaced by the <i>British Pharmacopoeia</i> (<i>Pharmacopoeia Britannica</i>), recommended and announced in the Medical Acts of 1858 and 1862, respectively, which appeared in 1864 and is still in use today. Mayerne was knighted by James I in 1624.
Disruption to the FOXO-PRDM1 axis resulting from deletions of chromosome 6 in acute lymphoblastic leukaemia
Authors: Paul B. Sinclair, Ruth E. Cranston, Prahlad Raninga, Joanna Cheng, Rebecca Hanna, Zoe Hawking, Steven Hair, Sarra L. Ryan, Amir Enshaei, Sirintra Nakjang, Vikki Rand, Helen J. Blair, Anthony V. Moorman, Olaf Heidenreich, Christine J. Harrison
Journal: Leukemia (2023)

Abstract A common problem in the study of human malignancy is the elucidation of cancer driver mechanisms associated with recurrent deletion of regions containing multiple genes. Taking B-cell acute lymphoblastic leukaemia (B-ALL) and large deletions of 6q [del(6q)] as a model, we integrated analysis of functional cDNA clone tracking assays with patient genomic and transcriptomic data, to identify the transcription factors FOXO3 and PRDM1 as candidate tumour suppressor genes (TSG). Analysis of cell cycle and transcriptomic changes following overexpression of FOXO3 or PRDM1 indicated that they co-operate to promote cell cycle exit at the pre-B cell stage. FOXO1 abnormalities are absent in B-ALL, but like FOXO3 , FOXO1 expression suppressed growth of TCF3::PBX1 and ETV6::RUNX1 B-ALL in-vitro. While both FOXOs induced PRDM1 and other genes contributing to late pre-B cell development, FOXO1 alone induced the key transcription factor, IRF4 , and chemokine, CXCR4 . CRISPR-Cas9 screening identified FOXO3 as a TSG, while FOXO1 emerged as essential for B-ALL growth. We relate this FOXO3-specific leukaemia-protective role to suppression of glycolysis based on integrated analysis of CRISPR-data and gene sets induced or suppressed by FOXO1 and FOXO3. Pan-FOXO agonist Selinexor induced the glycolysis inhibitor TXNIP and suppressed B-ALL growth at low dose (ID 50 &lt; 50 nM).
Nanofiber matrix formulations for the delivery of Exendin-4 for tendon regeneration: In vitro and in vivo assessment
Authors: Sama Abdulmalik, Jack Gallo, Jonathan Nip, Sara Katebifar, Michael Arul, Amir Lebaschi, Lucas N. Munch, Jenna M. Bartly, Shilpa Choudhary, Ivo Kalajzic, Yeshavanth Kumar Banasavadi-Siddegowdae, Syam P. Nukavarapu, Sangamesh G. Kumbar
Journal: Bioactive Materials (2023)

Tendon and ligament injuries are the most common musculoskeletal injuries, which not only impact the quality of life but result in a massive economic burden. Surgical interventions for tendon/ligament injuries utilize biological and/or engineered grafts to reconstruct damaged tissue, but these have limitations. Engineered matrices confer superior physicochemical properties over biological grafts but lack desirable bioactivity to promote tissue healing. While incorporating drugs can enhance bioactivity, large matrix surface areas and hydrophobicity can lead to uncontrolled burst release and/or incomplete release due to binding. To overcome these limitations, we evaluated the delivery of a peptide growth factor (exendin-4; Ex-4) using an enhanced nanofiber matrix in a tendon injury model. To overcome drug surface binding due to matrix hydrophobicity of poly(caprolactone) (PCL)-which would be expected to enhance cell-material interactions-we blended PCL and cellulose acetate (CA) and electrospun nanofiber matrices with fiber diameters ranging from 600 to 1000 nm. To avoid burst release and protect the drug, we encapsulated Ex-4 in the open lumen of halloysite nanotubes (HNTs), sealed the HNT tube endings with a polymer blend, and mixed Ex-4-loaded HNTs into the polymer mixture before electrospinning. This reduced burst release from ∼75% to ∼40%, but did not alter matrix morphology, fiber diameter, or tensile properties. We evaluated the bioactivity of the Ex-4 nanofiber formulation by culturing human mesenchymal stem cells (hMSCs) on matrix surfaces for 21 days and measuring tenogenic differentiation, compared with nanofiber matrices in basal media alone. Strikingly, we observed that Ex-4 nanofiber matrices accelerated the hMSC proliferation rate and elevated levels of sulfated glycosaminoglycan, tendon-related genes (Scx, Mkx, and Tnmd), and ECM-related genes (Col-I, Col-III, and Dcn), compared to control. We then assessed the safety and efficacy of Ex-4 nanofiber matrices in a full-thickness rat Achilles tendon defect with histology, marker expression, functional walking track analysis, and mechanical testing. Our analysis confirmed that Ex-4 nanofiber matrices enhanced tendon healing and reduced fibrocartilage formation versus nanofiber matrices alone. These findings implicate Ex-4 as a potentially valuable tool for tendon tissue engineering.
Vaccine-induced immune thrombotic thrombocytopenia
Authors: Douglas B. Cines, Andreas Greinacher
Journal: Blood (2023)

Within the first months of the COVID-19 vaccination campaign, previously healthy recipients who developed severe thrombosis (often cerebral and/or splanchnic vasculature) and thrombocytopenia typically after adenoviral vector-based vaccination were identified. Similarities between this syndrome, vaccine-induced immune thrombotic thrombocytopenia (VITT), and heparin-induced thrombocytopenia prompted recognition of the role of antiplatelet factor 4 (PF4) antibodies and management strategies based on IV immunoglobulin and nonheparin anticoagulants, which improved outcome. We update current understanding of VITT and potential involvement of anti-PF4 antibodies in thrombotic disorders.
Data From a One-Stop-Shop Comprehensive Cancer Screening Center
Authors: Ezra Bernstein, Shahar Lev-Ari, Shiran Shapira, Ari Leshno, Udi Sommer, Humaid Al-Shamsi, Meital Shaked, Ori Segal, Lior Galazan, Mori Hay-Levy, Miri Sror, Amira Harlap-Gat, Michael Peer, Menachem Moshkowitz, Ido Wolf, Eliezer Liberman, Gil Shenberg, Eyal Gur, Hanoch Elran, Gustavo Melinger, Jacob Mashiah, Ofer Isakov, Elad Zrifin, Nathan Gluck, Roy Dekel, Shlomi Kleinman, Galit Aviram, Arye Blachar, Ada Kessler, Orit Golan, Ravit Geva, Ofer Yossepowitch, Alfred I. Neugut, Nadir Arber
Journal: Journal of Clinical Oncology (2023)

Cancer is the second leading cause of death globally. However, by implementing evidence-based prevention strategies, 30%-50% of cancers can be detected early with improved outcomes. At the integrated cancer prevention center (ICPC), we aimed to increase early detection by screening for multiple cancers during one visit.Self-referred asymptomatic individuals, age 20-80 years, were included prospectively. Clinical, laboratory, and epidemiological data were obtained by multiple specialists, and further testing was obtained based on symptoms, family history, individual risk factors, and abnormalities identified during the visit. Follow-up recommendations and diagnoses were given as appropriate.Between January 1, 2006, and December 31, 2019, 8,618 men and 8,486 women, average age 47.11 ± 11.71 years, were screened. Of 259 cancers detected through the ICPC, 49 (19.8%) were stage 0, 113 (45.6%) stage I, 30 (12.1%) stage II, 25 (10.1%) stage III, and 31(12.5%) stage IV. Seventeen cancers were missed, six of which were within the scope of the ICPC. Compared with the Israeli registry, at the ICPC, less cancers were diagnosed at a metastatic stage for breast (none v 3.7%), lung (6.7% v 11.4%), colon (20.0% v 46.2%), prostate (5.6% v 10.5%), and cervical/uterine (none v 8.5%) cancers. When compared with the average stage of detection in the United States, detection was earlier for breast, lung, prostate, and female reproductive cancers. Patient satisfaction rate was 8.35 ± 1.85 (scale 1-10).We present a proof of concept study for a one-stop-shop approach to cancer screening in a multidisciplinary outpatient clinic. We successfully detected cancers at an early stage, which has the potential to reduce morbidity and mortality as well as offer substantial cost savings.[Media: see text].